ABSTRACT A primary challenge in the treatment of peritoneal malignancies, such as intraperitoneal mesothelioma and ovarian cancer, is preventing tumor recurrence in patients following the surgical removal of tumor (5-year survival <15% and <45%, respectively). Intraperitoneal administration of chemotherapy (e.g., paclitaxel) has been shown clinically to improve patient outcomes and prevent local tumor recurrence (the principal deterrent to long-term survival). However, despite these modest improvements, there are significant limitations to this therapy. For example, the current clinical formulation of paclitaxel (i.e., Taxol) is: A) limited due to toxic side effects resulting from absorption across the entire surface of the peritoneal cavity with no mechanism for tumor specificity; and, B) rapidly cleared from the peritoneal cavity (<10% remaining after 6 hours) resulting quickly in sub-therapeutic drug levels within the tumor tissue. The proposed project develops a novel, patented, technology, the expansile nanoparticle (eNP), designed to address these challenges and to target the primary observable cause of patient relapse (locally recurrent peritoneal tumors). eNPs decrease toxicity and increase efficacy via: a) unique Materials-Based Targeting, which leads to preferential and prolonged accumulation in tumors; and, b) triggered drug release following particle swelling, which occurs in response to exposure to lowered pH (5-6.5) found in the tumor microenvironment or in the endosomes of tumor cells. The results of our Phase I SBIR project include: 1) a radiolabeled biodistribution study demonstrating up to 65% of the injected dose of paclitaxel-loaded-eNPs (PTX-eNPs) accumulates in tumors via Materials-based Targeting, without the need for targeting ligands, and localization persists for up to 2 weeks; 2) PTX-eNPs deliver 10- to 100-fold higher intratumoral concentrations of paclitaxel than Taxol over a seven day period following injection; 3) PTX-eNPs reduce the amount of recurrent ovarian tumor by 3-fold (v. Taxol) and more than double survival (v. Taxol) in an orthotopic, multiple-dose, treatment of intraperitoneal mesothelioma model; and, 4) successful PTX-eNP production on the liter scale. This proposal addresses four activities on the critical path to obtaining an active IND application to evaluate PTX-eNPs in a Phase I clinical trial, including: Aim 1) Transfer of production processes and analytical methods for the eNP polymer to Norac Pharma (a contract manufacturing organization; CMO) followed by optimization of a scalable method and production of 1-2 kg of eNP polymer material; Aim 2) Transfer of production processes for the PTX-eNP to Particle Sciences (CMO) followed by optimization of a large-scale manufacturing method, production of PTX-eNPs for use in Aim 3 & 4 in vivo studies, development of analytics and stability testing; Aim 3) Perform a dose-escalation to determine the NOAEL and toxicity testing under current Good Laboratory Practices (cGLP) in rats; and, Aim 4) Perform a dose-escalation study of combined PTX-eNP and cisplatin in rats.